Kainate receptors (KARs) regulate the release of glutamate and GABA and synaptic plasticity in different brain regions involved in mood regulation, including the anterior-cingulate cortex, hippocampus, and amygdala. The KAR family includes five subunits: GluR5-7 and KA-1-2 (also called glutamate receptor ionotropic kainate (GRIK) 1-5 respectively). The receptors form hetereotrimers or homotrimers (GluR5-7 only). GluR5 and 6 can undergo RNA editing, resulting in altered channel permeability to different ions. The cell surface expression of the different KAR subunits is regulated by alternative splicing of receptor transcripts and trafficking properties of the receptor subtypes. The GluR6 gene is on chromosome 6q16.3-q21, a region of which has been implied in several bipolar disorder linkage studies. Recent genetic association studies directly implicates GluR6 as a contributing factor to increased risk of mood disorders. However, the roles of kainate receptors in mood regulation are largely unknown. Therefore we conducted studies in GluR5 and GluR6 knockout (KO) and wild-type control mice using a behavioral test battery for mood disorders and neurochemical experiments.<br>GluR5 and 6 KO mice appeared to attain normal growth, and lacked neurological abnormalities. Compared to WT and GluR5 KO mice, GluR6 KO consumed more saccharin sweeten solution, an indicator of hedonic activity. GluR6 KO traveled longer distances, entered and spent more time in the center of the open field (which can serve as indices for general activity as well as explorative-risk-taking activities). The hyperactivity of GluR6 KO persisted throughout the entire experimental period and they showed no habituation to the open-field arena. GluR6 KO exhibited aggressiveness in both the social interaction and resident-intruder tests. GluR6 KO had more activity in the open-arm of an elevated plus maze and less immobility in the forced swim test. GluR6 KO also exhibited higher responses in amphetamine challenge test. Thus, GluR6, but not GluR5, KO mice display behavioral excitement throughout experiments, greater aggressiveness, and hyperhedonia; these appear to phenocopy of the clinical manic state. Furthermore, chronic lithium treatment relieved key behavioral alterations of GluR6 KO mice including heightened locomotor activity, aggravated aggression and supersensitivity to amphetamine. Neurochemical experiments did not reveal any significant alterations of AMPA and NMDA receptors, however, hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. Taken together, the data strongly support the notion that GluR6 neurotransmission is a critical modulator of mood related behavior and that genetic dysfunction of GluR6 neurotransmission can result in behavioral display of mania-like behavior. Future studies are needed to elucidate the effects of human GluR6 SNPs on the function of GluR6 and related neurotransmission, brain regions involved in GluR6 medicated mood-like behavioral plasticity, and GluR6 as novel targets for developing mood affecting agents.[unreadable] Concerns that antidepressants (SSRIs) are potentially associated with suicidal thinking and/or behavior, especially in children and adolescents, led the FDA to issue a black box warning for those medications. The warning has resulted in decreased SSRI prescriptions in the young, with a concomitant increase in suicides in this population, emphasizing the need to identify the mechanisms whereby SSRIs may be associated with suicidal ideation in this population. Recent genetic studies show that the gene GRIK2 (which encodes for the GluR6 kainate receptor) confers sensitivity to treatment-emergent suicidal ideation in individuals with mood disorders. Additionally, the GRIK2 gene has been suggested to represent a bipolar susceptibility gene. Notably, antidepressants may be deleterious to bipolar disorder patients, because they may induce cycle acceleration, or cause agitation/dysphoria. Considering these and our findings with GluR6 KO mice, we hypothesized that mice (especially prepubertal mice) with altered GluR6 function would exhibit elevated levels of these behaviors as a response to SSRIs. [unreadable] [unreadable] Our preliminary data showed that aggression levels increased with age in all GluR6 genotype (WT, HET and KO) groups. Compared to GluR6 HET and WT mice, GluR6 KO mice exhibited elevated aggressive behavior. Two week citalopram treatment only increases aggression in GluR6 KO, but not WT mice. We are currently assessing the influence of citalopram on irritability and impulsivity behaviors in GluR6 KO mice.